Alcoholism in the United States is a serious health concern. Our long-term goal is to elucidate the mechanisms underlying alcohol addiction, a necessary prerequisite to the development of effective therapy. The specific hypothesis is that acute ethanol increases glutamate release via activation of dopamine D1 receptors (D1R). The increased glutamatergic transmission in turn modulates dopaminergic cell activity in the reward pathway and thus plays a significant role in the processes involved in alcohol addiction. We base this hypothesis on the following observations: a) clinically relevant concentrations of ethanol (10-80 mM) increase the amplitude of evoked excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors. In addition, ethanol reduces paired-pulse facilitation of evoked EPSCs and increased the frequency but not the amplitude of spontaneous EPSCs. Furthermore, ethanol increases extracellular glutamate levels in the ventral tegmental area (VTA) in midbrain slices and in vivo in rats; and b) the effects of ethanol are mimicked by a D1R agonist or a dopamine reuptake inhibitor, and they are blocked by a D1R antagonist or by depleting dopamine stores with reserpine. This hypothesis will be tested in the VTA of rats or mice by a combination of electrophysiological and pharmacological techniques. This includes measurements of extracellular glutamate and dopamine levels in both the VTA and the nucleus accumbens, in brain slices and/or in vivo. The Specific Aims are to determine: 1) The effects of ethanol on glutamatergic transmission to VTA dopamine neurons. We will compare AMPA receptor-mediated EPSCs and extracellular glutamate and dopamine levels in the absence and presence of ethanol. 2) The role of presynaptic D1Rs in the ethanol-induced increase in glutamatergic transmission to VTA dopamine neurons. We will compare the effects of ethanol on EPSCs and on extracellular glutamate levels in the absence and presence of a D1R agonist or antagonist. 3) The functional consequences of ethanol-mediated facilitation of glutamate release on the output of VTA dopamine neurons. We will determine whether glutamate antagonists: 1) attenuate the effects of ethanol on the excitability of VTA DA neurons, and 2) block the ability of systemic ethanol to increase dopamine release in the nucleus accumbens when the antagonists are infused into the VTA. PUBLIC HEALTH RELEVANCE The results of these studies will clarify a novel mechanism that is a significant component of the action of ethanol on the brain`s reward pathways. A better understanding of cellular mechanisms of alcohol addiction will improve the treatment and prevention of alcoholism. [unreadable] [unreadable] [unreadable]